The brain detects alterations in diet and energy balance, and through various neural circuits, regulates energy intake and energy expenditure. Dysfunction of these homeostatic mechanisms results in obesity, an epidemic problem in affluent societies. Identification of the neural circuits, as well as the molecular effectors operating within these circuits, is a major focus of obesity research. Based upon brain lesion studies, the ventromedial hypothalamus (VMH) has been proposed to play an important role in preventing obesity. Over time, this view fell out of favor, in part because of uncertainty regarding the anatomic specificity of crude, obesity-inducing lesions. More recently, interest in the VMH, as a site of body weight control, has increased. These recent developments, which point to a significant role for the VMH, include: 1) high-level expression of functionally active leptin receptors on VMH neurons, 2) abnormal VMH development and obesity in steroidogenic factor-1 (SF1) gene knockout mice, including mice with brain-specific SF1 gene knockout, 3) nutritional regulation of brain-derived neurotrophic factor (BDNF) in the VMH, 4) obesity in mice with genetic deficiency of BDNF, or its receptor, TrkB, and 5) development of obesity in mice lacking leptin receptors in the VMH (this application). Thus, substantial evidence makes a compelling argument that the VMH plays an important role in preventing obesity. This provides a unique opportunity for novel discoveries as the VMH, in the current "molecular age", has been underappreciated as a controller of energy homeostasis. With this in mind, the goal of the present application is to use genetic tools (cre/lox neuron-specific gene knockouts) to test the hypotheses that leptin signaling (Aim #1), BDNF expression (Aim #2), melanocortin receptor-4 (MC4R) signaling (Aim #3), and glutamatergic signaling (Aim #4) within the VMH, play important roles in preventing obesity. Novel discoveries of molecular pathways within the VMH that restrict body weight gain could identify new causes of obesity, as well as new therapies for this epidemic disease.